Chronic pain is a major contributor to disability and is the cause of much suffering. The successful treatment of severe and chronic pain is a primary goal of the physician, with opioid analgesics being preferred drugs for doing so.
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes are known as μ, δ and κ. As opiates have a high affinity for these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as enkephalins, endorphins and dynorphins.
Recent experimentation has led to the identification of a cDNA encoding an opioid receptor-like (ORL-1) receptor with a high degree of homology to the known receptor classes. The ORL-1 receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for μ, δ and κ, receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the term “orphan receptor”.
Subsequent research led to the isolation and structure of the endogenous ligand of the ORL-1 receptor (i.e., nociceptin). This ligand is a seventeen amino acid peptide structurally similar to members of the opioid peptide family.
The discovery of the ORL-1 receptor presents an opportunity in drug discovery for novel compounds that can be administered for pain management or other syndromes modulated by this receptor.
The publications “From Hit to Lead: Combining Two Complementary Methods” and “From Hit to Lead: Analyzing Structure-Profile Relationships” of Poulain et al. (J. Med. Chem. 44:3378-3390 and 3391-3401, respectively (2001)) describe carbamates and carbamate analogs for use as opioid receptor ligands.
International PCT Publication No. WO 95/03299 describes benzodiazepine derivatives for use as CCK or gastrin antagonists.
International PCT Publication No. WO 00/06545 A1 describes piperidine derivatives as high affinity ligands for the nociceptin receptor ORL-1.
International PCT Publication No. WO 01/07050 A1 describes substituted piperidines as nociceptin receptor ORL-1 agonists for use to treat cough.
International PCT Publication No. WO 01/34571 describes β-amino acid compounds for use in inhibiting β-amyloid peptide release.
International PCT Publication No. WO 02/080895 A2 describes farnesyl protein transferase inhibitors comprising bicyclic groups for use in treating malaria.
U.S. published patent application No. US 2003/0134846 by Windsor et al. describes farnesyl protein transferase inhibitors, some of which comprise bicyclic groups, for use in treating Trypanosoma Brucei infection.
U.S. published patent application No. US 2003/0149027 by Oi et al. describes benzodiazepine compounds for use in regulating somatostatin receptors.
U.S. published patent application No. US 2003/0207886 by Plücker et al. describes quinoxaline derivatives for use in protecting human epidermis or hair against uv radiation.
U.S. published patent application No. US 2004/0082784 by Sielecki-Dzurdz et al. describes pyridino and pyrimidino pyrazinones for use as corticotropin releasing factor receptor antagonists to treat anxiety and depression.
U.S. published patent application No. US 2004/0220177 by Kath et al. describes pyrimidine derivatives for use in treating abnormal cell growth in cancer.
Japanese Application No. JP 08/291,071 A2 and U.S. Pat. No. 5,283,244 by Sakamoto et al. each describe fused pyrazine derivatives for use, respectively, as stable injection solutions and glutamate antagonists.
U.S. Pat. Nos. 5,739,129 and 5,859,007 by Aquino et al. describe benzodiazepine derivatives for use as CCK or gastrin modulators.
U.S. Pat. Nos. 6,576,644 and 6,835,737 by Bi et al. describe aminoquinolines for use as inhibitors of cGMP phosphodiesterase.
U.S. Pat. No. 7,001,901 by Yang describes tetrazolylpropionamides for use as inhibitors of Aβ protein production.
Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.